1. Field of the Invention
The invention relates to the preservation of progenitor cells. More specifically, the invention relates to the in vivo or ex vivo preservation of progenitor cells, such as hematopoietic progenitor cells.
2. Summary of the Related Art
The wide variety of functionally and phenotypically different types of cells in a multi-cellular eukaryotic organism results in part from the proliferation and differentiation of rare and mostly quiescent populations of progenitor cells. For example, hematopoiesis involves the process of producing a balanced supply of different blood cells from such progenitor cells found in the adult bone marrow. The development of other cell types also depends upon production of the differentiated cells from such progenitor cells.
Progenitor cells are activated by signals, such as cell-cell contact or soluble regulators, to generate daughter cells that are identical to the parent (i.e., self-renewal of the parent) and/or to generate daughter cells that are more differentiated than the parent, thus beginning an irreversible process that ends with the production of differentiated, functional cells. In the process of hematopoiesis, differentiation is coupled to proliferation as a progenitor cell gives rise to more differentiated daughter cells that progressively become committed to producing only one blood cell type. The enormous activation of hematopoietic progenitor cells needed to meet the body's daily requirement for hundreds of billions of new mature blood cells is directed by potent soluble regulators (e.g., colony stimulating factors and cytokines) acting upon the hematopoietic progenitor cells themselves, and their more differentiated daughter cells.
Although progenitor cells eventually produce so many of the mature cells of the body, they occur only rarely. Moreover, typically the more primitive (i.e., undifferentiated) the progenitor cell, the more rare the progenitor cell. For example, the currently believed most primitive of the hematopoietic progenitor cells, which are called hematopoietic stem cells, occur at a frequency of only from about 1 in 10,000 to about 1 in 100,000 of the cells in the bone marrow. Hematopoietic stem cells have the capacity to generate more than 1013 mature blood cells of all lineages, including other progenitor cells which, although more differentiated than hematopoietic stem cells, are themselves capable of giving rise to several different types of mature blood cells.
Hematopoietic stem cells are responsible for sustaining blood cell production over the life of an animal. The small population of hematopoietic stem cells is sufficient to produce all the mature blood cells in a healthy individual; however, some unhealthy individuals suffer from a lack of a sufficient number of progenitor cells and/or mature blood cells. For example, cancer patients receiving chemotherapeutic or radiotherapy treatments designed to kill the rapidly dividing cancer cells also suffer from the depletion of white blood cells and platelets, thus exposing these patients to life-threatening opportunistic infections and bleeding episodes. Indeed, this hematopoietic progenitor cell-depleting activity is the dose-limiting factor for most of these chemotherapeutic and radiotherapeutic agents.
Many cancer patients are routinely treated with cytokines, including G-CSF, GM-CSF, SCF, Erythropoietin, and IL-11, to accelerate restoration of hematopoiesis following chemotherapy (Moore, M. A., Blood 78: 1-19, 1991). However, these cytokines lead to the irreversible differentiation of hematopoietic progenitor cells, including hematopoietic stem cells, into more differentiated daughter cells. Thus, better protection of hematopoietic progenitor cells is needed during chemotherapy.
Workers in the field have attempted to use cytokines in mice to protect progenitors from the toxicity of chemotherapy (Neta et al., J. Immunol. 136: 2483-2485, 1986; Neta et al., J. Immunol. 140: 108-111, 1988; Neta et al., J. Exp. Med. 173: 1177-1182, 1991; de Haan et al., Blood 87: 4581-4588, 1996; Lyman and Jacobsen, Blood 91: 1101-1134, 1998; Dalmau et al., Bone Marrow Transplant. 12: 551-563, 1993; Grzegorzewski et al., J. Exp. Med. 180: 1046-1057, 1994; Grzegorzewski et al., Blood 94:1066a (Abstr.)1999). Marshall et al. (Euro. J. Cancer 34: 1023-1029, 1998) and Gilmore et al. (Exp. Hematol. 27: 195-202, 1999) describe the use in clinical trials of a chemokine that allegedly inhibits progenitor cell proliferation, MIP1-α, as a chemoprotectant. Marshall (Marshall, A., Nat. Biotechnol. 16: 129, 1999) describes the use of MPIF-1, a chemokine that allegedly inhibits progenitor cell proliferation, in clinical trials as a chemoprotectant.
There are several drawbacks to using chemokines, cytokines, and other immmunoregulators as chemoprotectants during the chemotherapeutic or radiotherapeutic treatment of cancer patients. These drawbacks include the cost of production and toxicity to the patient.
Therefore, there is a need for improved reagents that are non-toxic and inexpensive to produce for use in preserving progenitor cells.